This mentored career award outlines a five-year training program for Dr. Ahuja's transition to scientific independence in the field of cancer biology. Dr. Ahuja proposes to expand her scientific skills and knowledge and it is expected that she would attain independent investigator status at the end of this award period. Dr. Ahuja will continue an established scientific mentorship with Dr. Baylin, an expert in epigenetics. She will also be mentored by Dr. Leach, an expert in pancreatic developmental biology and a fellow surgeon who will provide valuable clinical guidance. She has the full support of her Department to protect at least 75% of her time during the award period. Dr. Ahuja has laboratory and office space within Dr. Baylin's laboratory and is fully immersed in the research environment. The laboratory is located in the Cancer Research Buildings at Johns Hopkins and has access to many established scientists with an environment that favors collaboration and support of clinician scientists. The research plans focuses on understanding the role of DNA methylation in colorectal cancer metastases and recurrence and understand its applicability as translational markers. Epigenetic gene silencing involving aberrant DNA methylation of promoter-associated CpG islands functions as a central mechanism of inactivation of tumor-suppressor genes in colorectal cancer. We hypothesize that methylation profiles hold enormous potential as prognostic markers for recurrence in colorectal cancer and methylation profiles may allow molecular staging of colorectal cancer. In order to test these hypotheses, the following aims are proposed: 1) To utilize methylation profiles to predict recurrence in early-stage colon cancers. 2) To establish the methylation changes that underlie the process of metastasis in colorectal cancers in order to identify novel markers for predicting recurrence and metastases 3) To develop a molecular staging system for colorectal cancer. The research will build on exciting preliminary results demonstrating the utility of methylation profiles to predict recurrence. In addition, a systematic understanding of late events in colorectal carcinogenesis will be performed. Relevance: Colorectal cancer is a leading cause of cancer death worldwide and in the United States. The long-term goal of this proposal is to utilize knowledge of the newly emerging field, termed epigenetics, to establish novel markers for predicting patients at high-risk for colorectal cancer recurrence and to define novel cancer treatments.